Mucosal diseases such as Inflammatory Bowel Disease (IBD) result from changes in the microbiota (dysbiosis) in the face of ongoing inflammation. Our ongoing studies have identified a significant role for microbial-derived short chain fatty acids (SCFA) in intestinal disease and an important role for the transcriptional regulator hypoxia-inducible factor (HIF) in protection during intestinal inflammation. It remains unclear exactly how the host and the microbiota communicate and whether such communication is relevant to disease progression or inflammatory resolution. This study is designed to test the hypothesis that host-microbial crosstalk via SCFA promotes mucosal integrity, with HIF as the epithelial messenger and the epithelial IL-10R as the target. Three integrated specific aims are proposed to test this hypothesis. First, we will define the SCFA signaling axis for HIF stabilization using an established intestinal epithelial model in vitro and in vivo. Specifically, e will define how the epithelial SCFA signaling receptor GPR109a and impacts HIF stabilization in the mucosa and how such signaling promotes mucosal integrity. Second, we will elucidate the contribution of SCFA-induced HIF on epithelial IL-10R expression and signaling. Third, we will determine the relevance of this SCFA-HIF-IL-10R axis in mucosal inflammatory models. The overall aim of this proposal is to elucidate the host-microbial communication events mediating mucosal epithelial responses to inflammation.